Targeted at learning about inflammatory eye diseases, this project focused in FY 1998 on immunopathogenic processes in the eye and their modulation, as well as on the uveitogenicity of phylogenetically remote retinal antigens. Noteworthy results include the following: (1) Lymphocytes sensitized against self lens alpha B-crystallin were obtained by immunizing knockout mice, deficient in alpha B-crystallin with the deleted antigen. When injected into wild type mice, these lymphocytes produced severe inflammation in eyes in which the lens capsule was disrupted surgically or by a genetic manipulation. On the other hand, no inflammation was detected in eyes of untreated normal recipients. Moreover, no inflammation was induced by the sensitized cells in recipient eyes in which the cornea was damaged by cautering or in those in which the retinal pigment epithelium was destroyed by treatment with sodium iodate. These data underscore the efficiency of the lens capsule in protecting the lens fibers from immunological and other insults. (2) Linomide, a newly introduced immunomodulator, was found to inhibit the development of endotoxin-induced uveitis (EIU) in rats and mice. Unexpectedly, linomide treatment enhanced the production of proinflammatory cytokines, in particular interleukins - (IL-) 1 and -6. The latter effect may be related to the toxic effect of linomide, recently reported in patients treated with this compound. (3) Interphotoreceptor retinoid- binding protein (IRBP) from Xenopus laevis induced uveitis in Lewis rats, but only at doses approximately 50 fold higher than those of bovine IRBP. Two peptides derived from Xenopus IRBP (521-540 and 1180-1191) were also uveitogenic, but to a lesser degree than their homologs from human or bovine IRBP. Antibodies against bovine or Xenopus IRBP cross-reacted with the heterelogous protein. On the other hand, sensitized lymphocytes failed to detect any cross- reactivity between the proteins from the two species. Yet, lymphocytes sensitized against IRBP peptides 521-540 or 1180-1191 did recognize the corresponding peptide of IRBP from other species. These data indicate that the cellular immune response against an organ-specific protein from phylogenetically remote species is targeted mainly at peptides that are specific for the immunizing protein, rather than against peptides that are shared by the protein from other species.